1. Field
The present invention relates generally to therapeutic agents, formulations comprising them and their use in the treatment, amelioration and/or prophylaxis glioma brain tumours and related conditions.
2. Description of the Prior Art
Cancer is a significant human health problem throughout the world and is one of the largest single causes of mortality and morbidity. The term “cancer” describes an array of different diseases linked by cumulative multiple genetic mutations, which result in the activation of oncogenes and/or the inactivation of tumor suppressor genes. The cause and source of these mutations differs between different cancers of human body organs.
Cancer within the human brain constitutes a very specific, serious and commonly terminal disease, with a median survival in patients of less than 1 year, despite provision of the optimal treatment available. The very unique biological environment of the brain, as separated by the blood brain barrier (BBB), significantly contributes to a range of site-specific cancers in this organ that require alternative treatment than those cancers of the remaining human body.
Approximately 17,000 primary brain tumors are diagnosed in patients in the United States alone each year. Of these, approximately 60% are glioma tumors or ‘astrocytomas’ that arise from brain cells called astrocytes or their precursors. Astrocytes are cells in the central nervous system that support neuronal function. Astrocytomas can be graded by histologic features that signify increasing malignancy into astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme (GBM). Anaplastic astrocytoma and GBM are considered high-grade gliomas while the astrocytoma is considered to be a low-grade glioma. High-grade tumors grow rapidly and can easily infiltrate and spread through the brain. High-grade tumors are much more aggressive and require very intense therapy. The majority of astrocytic tumors in children are low-grade, whereas the majority in adults are high-grade. Astrocytomas can occur anywhere in the brain and spinal cord, however the majority are located in the cerebral hemispheres.
Patients with brain cancer most commonly present with seizures and a slowly progressive neurologic deficit, usually motor weakness. Alternatively, patients may present with generalized symptoms of increased intracranial pressure, including headaches, nausea and vomiting, and cognitive impairment.
Although advances have been made in detection and therapy of brain cancer diseases, no universally successful method for prevention or treatment is currently available. Current therapies for many brain cancers are generally based on a combination of chemotherapy or surgery and radiation and continue to prove inadequate in many patients.
For example, the treatment of glioma brain tumours remains difficult in that no contemporary treatments are curative. Treatments are non-curative primarily due to tumors being beyond the reach of local control when it is first detected clinically or radiographically. No significant advancements in the treatment of brain cancers have occurred in the past 25 years. Without therapy, patients with GBMs uniformly die within 3 months. Patients conversely treated with optimal therapy, including surgical resection, radiation therapy, and chemotherapy, have a median survival of approximately 1 year. Therefore, the treatment of patients with brain cancer is often palliative and encompasses and/or surgery, radiotherapy, and chemotherapy.
Radiation therapy in addition to surgery has been shown to prolong survival in patients with brain cancers compared to surgery alone, however the responsiveness of these cancers to radiotherapy varies. In many instances, radiotherapy can induce a phase of remission, often marked with stability or regression of neurologic deficits as well as diminution in the size of the contrast-enhancing mass. Unfortunately, any period of response is often short-lived in brain cancer because the tumor typically recurs within 1 year, resulting in further clinical deterioration.
Chemotherapeutic regimens for brain cancer have suggested that fewer than 25% of patients obtain a significant survival benefit from adjuvant chemotherapy. Carmustine (BCNU) and cis-platinum (cisplatin) have been the primary chemotherapeutic compounds used against malignant gliomas. All agents in use have no greater than a 30-40% response rate, and most fall into the range of 10-20%. A major hindrance to the use of chemotherapeutic compounds for brain tumours is the fact that the BBB effectively excludes many agents from the CNS. Despite initial attempts investigating the delivery of chemotherapeutic compounds via an intraarterial route rather than intravenously, no survival advantage has been observed.
The extent of surgery (biopsy versus resection) has been shown in a number of studies to affect length of survival. For example, patients with high-grade gliomas who had a gross total resection had a 2-year survival rate of 19%, while those with a subtotal resection had a 2-year survival rate of 0%.
As many brain cancers cannot be cured with surgery, the surgical goals are to establish a pathological diagnosis, relieve mass effect, and, if possible, achieve a gross total resection to facilitate adjuvant therapy.
Stereotactic biopsy followed by radiation therapy has been considered in certain circumstances. These include patients with a tumor located in an eloquent area of the brain; patients whose tumors have minimal mass effect or are infiltrating without discrete margins; and patients in poor medical condition, precluding general anesthesia. Median survival after stereotactic biopsy and radiation therapy is reported to be from 27-47 weeks.
In light of the foregoing, new approaches for the management of glioblastomas and other glioma brain tumours are critically necessary.